Natural prostaglandins have a unique chemical structure based on prostanoic acid (7-[(1S,2S)-2-octylcyclopentyl]heptanoic acid) and exhibit a broad range of physiological activities even when present in extremely small amounts. A large number of prostaglandin and prostaglandin analog-based drugs have been developed for a variety of medical indications. For example, tafluprost (ZIOPTAN), travoprost (TRAVATAN) and bimatoprost (LUMIGAN) are used topically (as eye drops) to treat glaucoma and ocular hypertension. Lubiprostone (AMITIZA) is used in the management of chronic constipation. Dinoprostone is a naturally occurring prostaglandin (PGE2) that is used in the clinic for the induction of labor in humans. Therefore, given the pharmaceutical importance of these compounds and their analogs, numerous methods have been developed and disclosed in both academia and industry for the manufacture of prostaglandins and structural analogs of prostaglandins.
An early approach useful for the synthesis of prostaglandin analog F2α and prostaglandin E2 was disclosed by E. J. Corey in 1969 (J. Am. Chem. Soc., 1969, 91, 5675-5676). This approach is referred to as the Corey method, and the well-known Corey lactone—which itself requires about 10 synthetic steps and contains all of the three prostaglandin E (PGE) stereochemical centers already in place—is pivotal to the Corey method. The ω- and α-hydrocarbon-based side chains are added sequentially by Horner-Wadsworth-Emmons and Wittig reactions (see FIG. 1). The Corey method and its more recent modifications and permutations are probably the most used and reported synthetic approaches for the industrial manufacture of prostaglandins and prostaglandin analogs. Disadvantages of this approach include, however, the high cost of the Corey lactone and the burdensome column chromatographic purification that are often required to remove undesired isomers and/or impurities.
Another approach that can be used to prepare prostaglandins and their analogs is sometimes referred to as the two-component approach (J. Am. Chem. Soc., 1972, 94, 3643-3644 and J. Am. Chem. Soc., 1972, 94, 7827-7832). The key characteristic of this approach is the installation of the ω-side chain using a 1,4-conjugate addition reaction of a vinyl organocopper or organocuprate reagent to a cyclopentenone system in which the α-side chain is already present (see FIG. 2). This method, which utilizes organocopper reagents, is referred to herein as the conventional two-component approach. There are many known methods for making α-side chain-substituted cyclopentenones that are useful in the conventional two-component approach. The conventional two-component approach has been used for the synthesis of a variety of prostaglandins and their analogs.
Fried. et. al. (J. Am. Chem. Soc. 1972, 94, 7827-7832), Lipshutz et al. (J. Am. Chem. Soc. 1988, 110, 2641-2643), Lipshutz, et. al. (J. Am. Chem. Soc. 1990, 112, 7440-7441) and Van Hijfte et al. (Tetrahedron 1992, 48, 6393-6402) have disclosed processes for preparing prostaglandin E1 (PGE1) using the two-component approach, in which various organocuprates, as vinylating agents, were coupled with cyclopentenones by 1,4-conjugate addition under cryogenic temperatures. Organotin reagents, orangolithium reagents, or organozirconium reagents are required as synthetic precursors to the above mentioned organocopper compounds used in the method.
U.S. Pat. No. 7,897,795 (the '795 patent) and U.S. Pat. No. 8,846,958 (the '958 patent) which were disclosed by the applicant, describe the utilization of the conventional two-component approach (see FIG. 2) for the syntheses of certain prostaglandin analogs (e.g., travoprost, bimatoprost, and lubiprostone). In certain processes disclosed in the '795 patent and the '958 patent, a 2-substituted-4-oxy-cyclopent-2-en-1-one intermediate II reacts with a higher order cuprate via 1,4-conjugate addition to give a 2,3-disubstituted-4-oxy-cyclopentan-1-one compound I. This compound, I, can be optionally modified and deprotected to provide various prostaglandin E and prostaglandin F analogs.
However, use of two-component approach is associated with a number of limitations and disadvantages including: the need for cryogenic temperatures (about −50 to −78° C.) in the 1,4-conjugate addition step; the use of organometallic compounds as precursors to the organocopper compounds such as organotin compounds, that are considered toxic and are difficult to purify, or organozirconium compounds, that are moisture sensitive and that can require cryogenic temperatures for their preparation; the use of reactive and difficult to handle organolithium compounds for the preparation of the organocopper compounds; and the need for multiple steps for conversion of the alkyne starting materials through to the requisite organocopper compounds. In addition, the cyanide in some of the cuprate reagents is toxic. The cuprates are not commercially available, due in part to their reactivity and instability under ambient conditions, including their sensitivity to air, which necessitates their immediate use upon synthesis. The reactivity of the cuprate is modulated, and can even be limited, by the electronic nature of substituents on the carbon skeleton adjacent to the copper atom. In fact, in some cases (e.g., tafluprost; see FIG. 4) the desired 1,4-conjugate addition reaction to α-side chain-substituted cyclopentenones does not work. Furthermore, the copper salt used to make the organocopper compounds is required in stoichiometric amounts.
Given the inefficient aspects and operational difficulties associated with the use of the conventional methods in the field to which the present invention pertains, there is a need for the development of a milder, less-toxic, cost-effective and user-friendly process for enantioselectively and diastereoselectively preparing prostaglandin analogs in good yields. Surprisingly, the present invention provides solutions to this and other problems in the relevant field to which the present invention pertains.